Hammersmith Hospital Research Articles

Experience of using gene replacement therapy with Zolgensma® (onasemnogene abeparvovec) in real clinical practice in Russia

Objective: to analyze the safety and evaluate the effectiveness of therapy with onasemnogene abeparvovec in patients with spinal muscular atrophy in real clinical practice based on the experience of using the drug in the neuromuscular center of Research Clinical Pediatric Institute of Pirogov Russian National Research Medical University.Materials and methods. Patients with spinal muscular atrophy received therapy with onasemnogene abeparvovec based on the prescription of the drug according to vital indications by a council of physicians of Federal institutions (the availability of the drug was carried out within the framework of the MAP Program (global program of managed access MAP to AVXS-101 for eligible patients in countries, where it is not approved by regulatory authorities (NCT03955679), through funding from the charitable foundations, as well as through funding from the state fund “Circle of Kindness”. The drug tolerance was assessed and the analysis of side effects after drug administration was based on the criteria for adverse events (General criteria Adverse Event Terminology (CTCAE) v. 5.0) Patient motor function was assessed prior to treatment initiation and every 3–6 months after therapy using the Philadelphia Pediatric Hospital’s CHOP INTEND scale, total motor development based on Hammersmith Hospital Neurological Assessment Scale in Young Children, Part 2 (HINE-2), and the acquisition of new motor skills.Results. 41 children aged 5 to 47 months (weighing no more than 21 kg) received therapy with onasemnogene abeparvovec in the period from April 2020 to December 2021. Adverse events (hyperthermia, decreased appetite, nausea, vomiting) were registered in all patients with different degree of severity. Elevated levels of transaminases greater than 2 times the upper limit of the normal range were observed in 32 patients (78 %), thrombocytopenia in 9 patients (22 %). 15 patients (36 %) required a dose adjustment of corticosteroids.17 patients underwent assessment of motor scales after 6 months, 10 children were assessed after a year. The average improvement on the HINE-2 scale was 3.3 / 4.4 points, respectively. The average improvement on the CHOP INTEND Scale was 7.1 / 9.4 points after 6 / 12 months of therapy.Conclusion. The efficacy and safety of onasemnogene abeparvovec have been demonstrated in real clinical practice in the treatment of spinal muscular atrophy for children in different age groups with a body weight of no more than 21 kg.

Historical aspects of muscle research in the Dubowitz Neuromuscular Centre: the Hammersmith days

Historical aspects of muscle research in the Dubowitz Neuromuscular Centre: the Hammersmith days

Dermot O’Brien Hourihane (1933–2020)

Dermot Hourihane was born in Ballina, County Mayo, but his family soon moved to Dublin where he was educated. He studied medicine at University College Dublin and interned at St...

In memory of Dr Maria Helena Gilleece MD, MBChB, BSc Hons (Biochem), MRCP, MRCPath, PGCMed (27th November 1959-24th June 2021).

In memory of Dr Maria Helena Gilleece MD, MBChB, BSc Hons (Biochem), MRCP, MRCPath, PGCMed (27th November 1959-24th June 2021).

Changes in Circulating Kisspeptin Levels During Each Trimester in Women With Antenatal Complications.

ContextAntenatal complications such as hypertensive disorders of pregnancy (HDP), fetal growth restriction (FGR), gestational diabetes (GDM), and preterm birth (PTB) are associated with placental dysfunction. Kisspeptin has emerged as a putative marker of placental function, but limited data exist describing circulating kisspeptin levels across all 3 trimesters in women with antenatal complications.ObjectiveWe aimed to assess whether kisspeptin levels are altered in women with antenatal complications.MethodsWomen with antenatal complications (n = 105) and those with uncomplicated pregnancies (n = 265) underwent serial ultrasound scans and blood sampling at the Early Pregnancy Assessment Unit at Hammersmith Hospital, UK, at least once during each trimester (March 2014 to March 2017). The women with antenatal complications (HDP [n = 32], FGR [n = 17], GDM [n = 35], PTB [n = 11], and multiple complications [n=10]) provided 373 blood samples and the controls provided 930 samples. Differences in circulating kisspeptin levels were assessed.ResultsThird-trimester kisspeptin levels were higher than controls in HDP but lower in FGR. The odds of HDP adjusted for gestational age, maternal age, ethnicity, BMI, smoking, and parity were increased by 30% (95% CI, 16%-47%; P < 0.0001), and of FGR were reduced by 28% (95% CI, 4-46%; P = 0.025), for every 1 nmol/L increase in plasma kisspeptin. Multiple of gestation-specific median values of kisspeptin were higher in pregnancies affected by PTB (P = 0.014) and lower in those with GDM (P = 0.020), but not significantly on multivariable analysis.ConclusionWe delineate changes in circulating kisspeptin levels at different trimesters and evaluate the potential of kisspeptin as a biomarker for antenatal complications.

Geriatrician-led care model in frail cardiology patients reduces re-admissions

As the population admitted under cardiology is likely to become frailer, a geriatrician-led model of post-procedural care similar to that used in orthopaedic surgery may be beneficial. In 2016, a new geriatrician-led ward was created in Hammersmith Hospital where frail cardiology patients could be transferred post-treatment. Using diagnostic coding, patients over the age of 65 years between 01 April and the 31 August for both 2016 and 2019 were identified, and data collected retrospectively from electronic patient records. An anonymised staff survey was completed following the introduction of the new service. Patients discharged from the geriatrician-led ward had fewer re-admissions than both cardiology-led wards in 2019 (chi-squared 5.46; p=0.02), and overall re-admissions in 2016 (chi-squared 4.34; p=0.037). The majority of surveyed respondents felt that this level of geriatrician input was useful. Geriatrician-led post-procedural care in cardiology reduced 30-day re-admissions in an elderly cohort.

In memoriam: John R. Mallard (1927-2021).

In memoriam: John R. Mallard (1927-2021).

Nigel Standfield: vascular surgeon who trained generations worldwide

Nigel Standfield was born in Wuppertal, Germany, to John Standfield, who had served in the British and Indian armies during the second world war and then in British intelligence, and...

Editorial introductions.

Editorial introductions.

Irvin Alexander Lampert

Irvin Alexander Lampert was born in Johannesburg to fairly orthodox Jewish parents. After qualifying he did house jobs at Johannesburg General Hospital and Baragwanath Hospital, Soweto, during a famine before...

Transcriptional analysis of multiple ovarian cancer cohorts reveals prognostic and immunomodulatory consequences of ERV expression

BackgroundEndogenous retroviruses (ERVs) play a role in a variety of biological processes, including embryogenesis and cancer. DNA methyltransferase inhibitors (DNMTi)-induced ERV expression triggers interferon responses in ovarian cancer cells via...

The efficacy and safety of nusinersen within the expanded access program in Russia

Introduction.Spinal muscular atrophy is a severe neuromuscular disease characterized by rapid progression of muscle weakness and earlydeath. Pathogenetic therapy with nusinersen can significantly change the course of the disease and enable the patient to acquire new skills.The study of the efficacy and safety of nusinersen therapy in patients with type 1 spinal muscular atrophy should be continued.Theaim of the studywas to assess the safety and efficacy of nusinersen therapy in patients with type 1 spinal muscular atrophy for 6 monthsas part of an expanded access program at federal and regional healthcare facilities.Materials and methods.Patients with type 1 spinal muscular atrophy received nusinersen therapy under the expanded access program(NCT02865109). Patients were evaluated before starting treatment and 6 months after starting treatment. Overall motor development andmotor function was assessed using the Hammersmith Infant Neurological Status Scale Part 2 and the Philadelphia Pediatric Hospital Neonatal Motor Scale.Results.41 children aged 6 to 38 months received nusinersen therapy between July 2019 and March 2020. At the time of analysis, all patients were alive and continued treatment. The average improvement on the Hammersmith Hospital Neurological Status Scale was 3.7 pointsafter 6 months of therapy compared to baseline (n = 39, p &lt;0.001). The mean improvement on the Children’s Hospital of PhiladelphiaScale for the Diagnosis of Motor Function in Newborns was 9.8 after 6 months of therapy from baseline (n = 30, p &lt;0.001).Conclusion.The efficacy and safety of nusinersen have been demonstrated in real clinical practice in Russia in the treatment of early-onsetspinal muscular atrophy.

Confronting a rare ovarian cancer during lockdown

Confronting a rare ovarian cancer during lockdown

Paroxysmal nocturnal haemoglobinuria (PNH): novel therapies for an ancient disease.

In the UK, early work on paroxysmal nocturnal haemoglobinuria (PNH) was conducted by John Dacie who, at the Hammersmith Hospital, first hypothesised that the PNH abnormality might arise through a somatic mutation; and who outlined with S.M. Lewis the relationship between PNH and aplastic anaemia. When the phosphatidylinositol glycan anchor biosynthesis Class A (PIGA) gene was identified by Taroh Kinoshita's group, jointly with him the Hammersmith group proved that PNH is caused in most patients by a single somatic mutation in the PIGA gene. At the same time, after Bruno Rotoli had spent a sabbatical at the Hammersmith, the 'immune escape model' for the pathogenesis of PNH was developed. Early this century, Peter Hillmen, formerly at the Hammersmith and now in Leeds, spearheaded the use of the complement-blocking (anti-C5) antibody eculizumab. This new medicine radically changed the management and the clinical course of patients with PNH. Recently a derivative of eculizumab with more favourable pharmacokinetics has been introduced. In view of the fact that these agents are associated with C3-dependent extravascular haemolysis, it is important that a number of inhibitors of the proximal complement pathway are now in the offing and may further improve the life of patients with PNH.

Cardiopulmonary exercise testing as a guideline indicator for mitral valve intervention

Abstract Background Primary mitral regurgitation (MR) is one of the most common heart valvular pathologies. However, optimum timing of surgery remains controversial. Purpose To describe changes in cardiopulmonary exercise testing (CPET) parameters after surgery for severe primary MR. Methods In a single centre prospective study, patients undergoing surgery under current ESC guidelines for severe primary MR underwent assessment with transthoracic echocardiogram, CPET, cardiac MRI and quality of life questionnaire pre-operatively and at six months after surgery. The primary outcome was a per protocol analysis of impaired post-operative functional capacity (defined as post-operative left ventricular ejection fraction on transthoracic echocardiogram &amp;lt;50% and/or post-operative percentage predicted peak VO2 ≤84%). Results 43 of the 50 patients recruited between February 2017 and October 2018 were included in the per protocol analysis. Thirty five patients (72.9%) had impaired post-operative functional capacity. In the overall cohort (n=43), there was a significant fall post-operatively in percentage predicted peak VO2 (ppVO2) (81.8±15.7% vs. 76.2±16.2%, p&amp;lt;0.01) and anaerobic threshold (AT) (48.0±11.1% vs. 44.3±10.1%, p=0.01). In patients with a class I indication for surgery (n=30), there was no significant change post-operatively in ppVO2 (79.6±15.7% vs. 75.6±16.7%, p=0.09) or AT (49.9±11.4% vs. 46.4±10.2%, p-0.09). However, in patients with a class II indication for surgery (n=13), there was a significant change post-operatively in ppVO2 (86.9±15.1% vs. 77.4±15.9%, p&amp;lt;0.01), but not in AT (43.5±9.6% vs. 39.5±8.3%, p=0.16). In the multivariable analysis, pre-operative left ventricular ejection fraction ≤60% (hazard ratio, 1.69; 95% confidence interval, 1.56 to 480.1, p=0.04) and pre-operative percentage predicted peak VO2 ≤84% (hazard ratio, 1.22; 95% confidence interval, 2.13 to 107.1, p&amp;lt;0.01) were independent predictors for impaired post-operative functional capacity. Conclusions Pre-operative percentage predicted peak VO2 ≤84% is an independent predictor of impaired post-operative functional capacity. Subject to a confirmatory study, this may help to refine current ESC guidelines for intervention for severe primary MR. Change in ppVO2 after surgery Funding Acknowledgement Type of funding source: Foundation. Main funding source(s): Rosetrees Trust and Friends of Hammersmith Hospital

Feasibility of a 3 mm arteriotomy for brachiocephalic fistula formation.

The arteriovenous fistula is the modality of choice for long-term haemodialysis access. We describe the feasibility of routinely fashioning a brachiocephalic fistula utilising a 3 mm long arteriotomy in an attempt to reduce the incidence of symptomatic steal syndrome yet while maintaining satisfactory clinical outcomes. All patients who underwent brachiocephalic fistula formation using a routine 3 mm long arteriotomy within Hammersmith Hospital between January 2017 and March 2018 were included. Primary outcomes included primary failure, failure of maturation, secondary patency and steal syndrome. Sixty-eight brachiocephalic arteriovenous fistula were fashioned utilising a 3 mm long arteriotomy during the study period. Mean age was 60.5 years with 59% having a history of diabetes mellitus. Mean followup was 368 days. Primary failure occurred in 10 (14.7%) patients. Cannulation was achieved in 67.3% of remaining fistula within 3-months, rising to 87.3% by 6-months. Primary patency at 6 and 12 months was 76% and 69%, respectively. Secondary patency at 6 and 12 months was 94% and 91%, respectively. Dialysis access steal syndrome was clinically apparent in three (4.4%) patients with all cases being managed conservatively. A 3 mm long arteriotomy may be routinely utilised for brachiocephalic fistula creation in an attempt to limit the incidence of steal syndrome yet while maintaining clinical patency outcomes.

Left ventricular speckle tracking echocardiographic evaluation before and after TAVI

Aims: To assess left ventricular (LV) function before and after transcatheter aortic valve implantation (TAVI) using conventional echocardiographic parameters and global longitudinal LV strain (GLS) and compare outcomes between Edwards S3 and Evolut R valves.Methods and results: Data were collected for consecutive patients undergoing TAVI at Hammersmith hospital between 2015 and 2018. Of the 303 patients, those with coronary artery disease and atrial fibrillation were excluded leading to a total of 85 patients, which constituted our study group. The mean follow-up was 49 ± 39 days. In total, 60% of patients were treated with Edwards S3 and 40% Evolut R. TAVI resulted in an early improvement of GLS (−13.96 to −15.25%, P = 0.01) but not ejection fraction (EF) (47.6 to 50.1%, P = 0.09). LV mass also improved, especially in patients with marked baseline LV hypertrophy (P < 0.001). There were no appreciable differences of LV function improvement and overall LV remodelling after TAVI between the two types of valves used (P = 0.14).Conclusions: TAVI results in reverse remodelling and improvement of GLS, especially in patients with impaired baseline LV function. There were no differences in the extent of LV function improvement between Edwards S3 and Evolut R valves but there was a greater incidence of aortic regurgitation with Evolut R.

Professor Ian Aird: Master of surgical education.

Ian Aird (1905-1962) was a Scottish surgeon renowned for his textbook: "A companion in surgical studies", a uniquely single-author work of thousands of pages. It was an essential study for young surgeons aspiring to pass the FRCS (Edin) examination. He was appointed Chair of Surgery of the Royal Postgraduate Medical School at Hammersmith Hospital in London. Under his direction, his faculty developed a pump oxygenator, used it successfully for the first time in a patient and introduced cardiac surgery in Russia. They also pioneered kidney transplantation in Britain. Aird himself discovered the relationship of blood groups to cancer and peptic ulceration. He became famous for the surgical separation of conjoined twins from Nigeria, fame that created conflicts with medical authority on the issue of cooperating with the press. He became frustrated when the medical council refused to support and sponsor funding for research. Sadly, even his indomitable energy and brilliance could not see him through his depression. He committed suicide at the age of 57.

Eric Bywaters a life story: 1 June 1910 to 2 April 2003

In the early 1990s I regularly attended the Executive and Finance Committee of the charity then known as the Arthritis Research Campaign and was delighted to have the opportunity to...

Ronald Wellesley Pigott: plastic surgeon who specialised in cleft lip and palate repairs

Ronald Wellesley Pigott was born in Isfahan, Persia (now Iran), the son of a general practitioner who settled in Kettering, Northamptonshire. He attended Oakham School. His friend and colleague, Brian...